The present invention relates generally to a series of novel small molecules, their synthesis and their use in the treatment of inflammatory disease.
Research spanning the last decade has helped to elucidate the molecular events attending cell-cell interactions in the body, especially those events involved in the movement and activation of cells in the immune system. See generally, Springer, T. Nature, 1990, 346, 425-434. Cell surface proteins, and especially the Cellular Adhesion Molecules (xe2x80x9cCAMsxe2x80x9d) and xe2x80x9cLeukointegrinsxe2x80x9d, including LFA-1, MAC-1 and gp 150.95 (referred to in WHO nomenclature as CD18/CD11a, CD18/CD11b, and CD18/CD11c, respectively) have correspondingly been the subject of pharmaceutical research and development having as its goal the intervention in the processes of leukocyte extravasation to sites of injury and leukocyte movement to distinct targets. For example, it is presently believed that prior to the leukocyte extravasation, which is a mandatory component of the inflammatory response, activation of integrins constitutively expressed on leukocytes occurs and is followed by a tight ligand/receptor interaction between integrins (e.g., LFA-1) and one or several distinct intercellular adhesion molecules (ICAMs) designated ICAM-1, ICAM-2, ICAM-3 or ICAM-4 which are expressed on blood vessel endothelial cell surfaces and on other leukocytes. The interaction of the CAMs with the Leukointegrins is a vital step in the normal functioning of the immune system. Immune processes such as antigen presentation, T-cell mediated cytotoxicity and leukocyte extravasation all require cellular adhesion mediated by ICAMs interacting with the Leukointegrins. See generally Kishimoto, T. K.; Rothlein; R. R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M.; Springer, T. Current Biology, 1994, 4, 506-532.
A group of individuals has been identified which lack the appropriate expression of Leukointegrins, a condition termed xe2x80x9cLeukocyte Adhesion Deficiencyxe2x80x9d (Anderson, D. C.; et al., Fed. Proc. 1985, 44, 2671-2677 and Anderson, D. C.; et al., J. Infect. Dis. 1985, 152, 668-689). These individuals are unable to mount a normal inflammatory and/or immune response(s) due to an inability of their cells to adhere to cellular substrates. These data show that immune reactions are mitigated when lymphocytes are unable to adhere in a normal fashion due to the lack of functional adhesion molecules of the CD18 family. By virtue of the fact that LAD patients who lack CD18 cannot mount an inflammatory response, it is believed that antagonism of CD18, CD11/ICAM interactions will also inhibit an inflammatory response.
It has been demonstrated that the antagonism of the interaction between the CAMs and the Leukointegrins can be realized by agents directed against either component. Specifically, blocking of the CAMs, such as for example ICAM-1, or the Leukointegrins, such as for example LFA-1, by antibodies directed against either or both of these molecules effectively inhibits inflammatory responses. In vitro models of inflammation and immune response inhibited by antibodies to CAMs or Leukointegrins include antigen or mitogen-induced lymphocyte proliferation, homotypic aggregation of lymphocytes, T-cell mediated cytolysis and antigen-specific induced tolerance. The relevance of the in vitro studies are supported by in vivo studies with antibodies directed against ICAM-1 or LFA-1. For example, antibodies directed against LFA-1 can prevent thyroid graft rejection and prolong heart allograft survival in mice (Gorski, A.; Immunology Today, 1994, 15, 251-255). Of greater significance, antibodies directed against ICAM-1 have shown efficacy in vivo as anti-inflammatory agents in human diseases such as renal allograft rejection and rheumatoid arthritis (Rothlein, R. R.; Scharschmidt, L., in: Adhesion Molecules; Wegner, C. D., Ed.; 1994, 1-38, Cosimi, C. B.; et al., J. Immunol. 1990, 144, 4604-4612 and Kavanaugh, A.; et al., Arthritis Rheum. 1994, 37, 992-1004) and antibodies directed against LFA-1 have demonstrated immunosuppressive effects in bone marrow transplantation and in the prevention of early rejection of renal allografts (Fischer, A.; et al., Lancet, 1989, 2, 1058-1060 and Le Mauff, B.; et al., Transplantation, 1991, 52, 291-295).
It has also been demonstrated that a recombinant soluble form of ICAM-1 can act as an inhibitor of the ICAM-1 interaction with LFA-1. Soluble ICAM-1 acts as a direct antagonist of CD18,CD11ICAM-1 interactions on cells and shows inhibitory activity in in vitro models of immune response such as the human mixed lymphocyte response, cytotoxic T cell responses and T cell proliferation from diabetic patients in response to islet cells (Becker, J. C.; et al., J. Immunol. 1993, 151, 7224 and Roep, B. O.; et al., Lancet, 1994, 343, 1590).
Thus, the prior art has demonstrated that large protein molecules which antagonize the binding of the CAMs to the Leukointegrins have therapeutic potential in mitigating inflammatory and immunological responses often associated with the pathogenesis of many autoimmune or inflammatory diseases. However proteins have significant deficiencies as therapeutic agents, including the inability to be delivered orally and potential immunoreactivity which limits the utility of theses molecules for chronic administration. Furthermore, protein-based therapeutics are generally expensive to produce.
Several small molecules have been described in the literature which affect the interaction of CAMs and Leukointegrins. A natural product isolated from the root of Trichilia rubra was found to be inhibitory in an in vitro cell binding assay (Musza, L. L.; et al., Tetrahedron, 1994, 50, 11369-11378). One series of molecules (Boschelli, D. H.; et al., J. Med. Chem. 1994, 37, 717 and Boschelli, D. H.; et al., J. Med. Chem. 1995, 38, 4597-4614) was found to be orally active in a reverse passive Arthus reaction, an induced model of inflammation that is characterized by neutrophil accumulation (Chang, Y. H.; et al., Eur. J. Pharmacol. 1992, 69, 155-164). Another series of molecules was also found to be orally active in a delayed type hypersensitivity reaction in rats (Sanfilippo, P. J.; el al., J. Med. Chem. 1995, 38, 1057-1059). All of these molecules appear to act nonspecifically, either by inhibiting the transcription of ICAM-1 along with other proteins or act intracellularly to inhibit the activation of the Leukointegrins by an unknown mechanism. None of the molecules directly antagonize the interaction of the CAMs with the Leukointegrins. Due to lack of potency, lack of selectivity and lack of a specific mechanism of action, the described small molecules are not likely to be satisfactory for therapeutic use.
It follows that small molecules having the similar ability as large protein molecules to directly and selectively antagonize the binding of the CAMs to the Leukointegrins would make preferable therapeutic agents. WO9839303 discloses a class of small molecule inhibitors of the interaction of LFA-1 and ICAM-1. WO9911258 discloses that the fungal metabolite mevinolin and derivatives bind to LFA-1 and disrupt the interaction of LFA-1 and ICAM-1. WO9949856 discloses a class of peptidomimetic inhibitors of ICAM binding to LFA-1 and Mac-1.
A first aspect of the invention comprises a method for treating or preventing inflammatory and immune cell-mediated diseases by the administration of certain novel small molecules. These compounds act by inhibiting the interaction of cellular adhesion molecules, specifically by antagonizing the binding of human intercellular adhesion molecules (including ICAM-1, ICAM-2 and ICAM-3) to the Leukointegrins (especially CD18/CD11a). A second aspect of the invention comprises novel small molecules having the above-noted therapeutic activities. A third aspect of the invention comprises methods for making these novel compounds. A final aspect of the invention comprises pharmaceutical compositions comprising the above-mentioned compounds suitable for the prevention or treatment of inflammatory and immune cell-mediated conditions.
In its first and broadest aspect, the invention comprises compounds of the formula I 
wherein:
wherein:
A1 is xe2x95x90Nxe2x80x94 or xe2x95x90C(H)xe2x80x94;
A2 is xe2x95x90Nxe2x80x94, xe2x95x90C(H)xe2x80x94, or xe2x95x90C(Rxe2x80x2)xe2x80x94 wherein Rxe2x80x2 is halogen, xe2x80x94CN, xe2x80x94Oalkyl, xe2x80x94CO2alkyl or -SO2alkyl, wherein the foregoing alkyl moieties are of 1 to 3 carbon atoms;
D is xe2x95x90Nxe2x80x94, xe2x95x90C(R1)xe2x80x94, xe2x95x90C(H)xe2x80x94, xe2x95x90C(SO2R1)xe2x80x94, xe2x95x90C(S(O)R1)xe2x80x94, xe2x95x90C(C(O)R1)xe2x80x94, xe2x95x90C(C(O)H)xe2x80x94, xe2x95x90C(SR1a)xe2x80x94, xe2x95x90C(OR1a)xe2x80x94 or xe2x95x90C(NHR1a)xe2x80x94,
xe2x80x83wherein R1 is selected from the class consisting of:
(A) xe2x80x94R100, which is:
xe2x80x83branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogen atoms are optionally and independently replaced with:
(i) halogen,
(ii) oxo,
(iii) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl or heteroaryl group are optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) -PO(OH)2,
(e) a group of the formula xe2x80x94COOR8, wherein R8 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR9R10, wherein R9 and R10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R9 and R10 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR11R12, wherein R11 and R12 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R11 and R12 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94Hxe2x80x94, or xe2x80x94NMexe2x80x94,
(h) a group of the formula xe2x80x94OR13, wherein R13 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR14, wherein R14 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) xe2x80x94CN, or
(k) an amidino group of the formula 
xe2x80x83wherein R15, R16 and R17 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R15, R16 and R17 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(l) halogen,
(m) a group of the formula xe2x80x94NHCONHalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,
(n) a group of the formula xe2x80x94NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,
(iv) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(v) xe2x80x94CN,
(vi) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94Hxe2x80x94, or xe2x80x94Mexe2x80x94,
(vii) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety contains 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(viii) a group of the formula xe2x80x94SR22, wherein R22 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe and xe2x80x94Me2,
(ix) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) straight or branched alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2,
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or
(e) a group of the formula xe2x80x94(CH2)nCONHR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
(x) a quaternary group of the formula 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x80x94 is a pharmaceutically acceptable counter ion,
(xi) a saturated, or partially unsaturated heterocyclic group consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally mono- or polysubstituted with oxo, and
(xii) a cycloalkyl group of 3 to 7 carbon atoms,
(B) branched or unbranched carboxylic acid groups of 3 to 6 carbon atoms,
(C) branched or unbranched phosphonic acid groups of 2 to 6 carbon atoms,
(D) branched or unbranched sulfonic acid groups of 2 to 6 carbon atoms,
(E) amidino groups of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(F) guanidino groups of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6, and R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl or heteroaryl group are optionally and independently replaced with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR36, wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms, (vi) a group of the formula xe2x80x94NR37R38, wherein R37 and R38 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR39R40, wherein R39 and R40 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R40 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(viii) a group of the formula xe2x80x94OR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(x) xe2x80x94CN, or
(xi) an amidino group of the formula 
xe2x80x83wherein R43, R44 and R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) groups of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, phenyl which is optionally mono- or polysubstituted with halogen, or R100, wherein R100 is as hereinbefore defined,
(I) saturated or unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, or bicyclic heterocyclic groups consisting of 8 to 11 atoms selected from N, O, C and S, including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally mono- or poly-substituted with moieties selected from the class consisting of:
(i) oxo,
(ii) xe2x80x94OR10, wherein R101 is:
(a) a hydrogen atom,
(b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of said alkyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR110 (wherein R110 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(c) acyl of 1 to 7 carbons, wherein any hydrogen atom of said acyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR111 (wherein R111 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(d) xe2x80x94CONR102R103, wherein R102 and R103 are each independently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R102 and R103 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94, or
(e) xe2x80x94COOR104, wherein R104 is alkyl of 1 to 7 atoms,
(iii) xe2x80x94CONR105R106, wherein R105 and R106 are each independently:
(a) a hydrogen atom,
(b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms,
(c) benzoyl,
(d) benzyl or
(e) phenyl, wherein said phenyl ring is optionally mono- or polysubstituted with xe2x80x94OR112, wherein R112 is alkyl of 1 to 6 carbon atoms,
xe2x80x83or, wherein R105 and R106 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94Hxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) xe2x80x94COOR107, wherein R107 is a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms,
(v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, wherein one or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) oxo,
(b) xe2x80x94OH,
(c) xe2x80x94OR113, wherein R113 is alkyl of 1 to 6 carbon atoms,
(d) xe2x80x94OCOCH3,
(e) xe2x80x94NH2,
(f) xe2x80x94NHMe,
(g) xe2x80x94NMe2,
(h) xe2x80x94CO2H, and
(i) xe2x80x94CO2 R114 wherein R114 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,
(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or more hydrogen atoms of said acyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) xe2x80x94OH,
(b) xe2x80x94OR115, wherein R115 is alkyl of 1 to 6 carbon atoms,
(c) xe2x80x94NH2,
(d) xe2x80x94NHMe,
(e) xe2x80x94NMe2,
(f) xe2x80x94NHCOMe,
(g) oxo,
(h) xe2x80x94CO2R116, wherein R116 is alkyl of 1 to 3 carbon atoms,
(i) xe2x80x94CN,
(j) the halogen atoms,
(k) heterocycles selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, and
(l) aryl or heteroaryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
(vii) xe2x80x94SO2R108, wherein R108 is:
(a) aryl or heteroaryl which is selected from the group consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR117 (wherein R117 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR118 (wherein R118 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR119 (wherein R119 is hydrogen or alkyl of 1 to 6 carbon atoms),
(viii) xe2x80x94COR109, wherein R109 is:
(a) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR120 (wherein R120 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl is optionally substituted with one or more halogen, straight or branched alkyl of 1 to 6 carbons, or xe2x80x94OR121 (wherein R121 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR122 (wherein R122 is hydrogen or alkyl of 1 to 6 carbon atoms),
(ix) xe2x80x94CHO,
(x) the halogen atoms, and
(xi) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
(J) the halogen atoms, and
(K) xe2x80x94CN, and
xe2x80x83wherein R1a is R100;
X is an oxygen or sulfur atom;
R3 is:
(A) a hydrogen atom, or
(B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group is optionally substituted with:
(i) a group of the formula xe2x80x94OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(ii) a group of the formula xe2x80x94NR49R50, wherein R49 and R50 are each, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of 1 to2 carbon atoms;
R4 is a group of the formula xe2x80x94(CR51R52)x(CR53R54)yR55, wherein,
x is  or 1,
y is 0 or 1,
R51, R52 and R53 are each, independently:
(A) a hydrogen atom,
(B) a group of the formula xe2x80x94OR56, wherein R56 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(C) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
R54 is:
(A) a group of the formula R57, wherein R57 is independently selected from the same class as is R1, or
(B) a group of the formula xe2x80x94OR58, wherein R58 is independently selected from the same class as is R1;
R55 is:
xe2x80x83aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more of the hydrogen atoms of said aryl or heteroaryl group is optionally and independently replaced with:
(A) R59, which is aryl or heteroaryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more of the hydrogen atoms of said aryl or heteroaryl group is optionally and independently replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- or polysubstituted with halogen or oxo,
(ii) a group of the formula xe2x80x94COOR60, wherein R60 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(iii) a group of the formula xe2x80x94NR61R62, wherein R61 and R62 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R61 and R62 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(iv) a group of the formula xe2x80x94CONR63R64, wherein R63 and R64 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R63 and R64 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(v) a group of the formula xe2x80x94OR65, wherein R65 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(vi) a group of the formula xe2x80x94SR66, wherein R66 is a hydrogen atom, or an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(vii) xe2x80x94CN,
(viii) nitro, or
(ix) halogen,
(B) methyl, which is optionally mono- or polysubstituted with fluorine atoms and additionally is optionally monosubstituted with R59,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94NR68R69, wherein R68 and R69 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R68 and R69 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R68 and R69 may additionally be the group R59,
(F) a group of the formula xe2x80x94CONR70R71, wherein R70 and R71 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R70 and R71 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R70 and R71 may additionally be the group R59,
(G) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R59,
(H) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(I) a group of the formula xe2x80x94SR74, wherein R74 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59,
(J) xe2x80x94CN,
(K) nitro, or
(L) halogen;
R5 is Cl or trifluoromethyl;
Z is xe2x95x90Nxe2x80x94 or xe2x95x90C(R6)xe2x80x94 wherein R6 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; and,
R7 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, xe2x80x94CN, nitro or trifluoromethyl, with the condition that when Z is xe2x95x90Nxe2x80x94 or xe2x95x90C(H)xe2x80x94, R7 is chlorine, trifluoromethyl, xe2x80x94CN or nitro;
and pharmaceutically acceptable salts thereof.
As the term is used herein, a xe2x80x9cpharmaceutically acceptable counter ionxe2x80x9d is any counter ion generally regarded by those skilled in the pharmaceutical art as being pharmaceutically acceptable. For a discussion of what are pharmaceutically acceptable counter ions, reference may be had to Stephen M. Bergle, Lyle D. Bighley and Donald C. Monkhouse, xe2x80x9cPharmaceutical Saltsxe2x80x9d, Journal of Pharmaceutical Sciences, 66 (1977), 1-19. By way of non-limiting example, the chloride, bromide, acetate, and sulphate ions are pharmaceutically acceptable counter ions.
Preferred are compounds of the formula I wherein:
A1 is xe2x95x90Nxe2x80x94 or xe2x95x90C(H)xe2x80x94;
A2 is xe2x95x90Nxe2x80x94, xe2x95x90C(H)xe2x80x94, or xe2x95x90C(Rxe2x80x2)xe2x80x94 wherein Rxe2x80x2 is halogen, xe2x80x94CN, xe2x80x94Oalkyl, xe2x80x94CO2alkyl or xe2x80x94SO2alkyl, wherein the foregoing alkyl moieties are of 1 to 3 carbon atoms;
D is xe2x95x90Nxe2x80x94, xe2x95x90C(R1)xe2x80x94, xe2x95x90C(H)xe2x80x94, xe2x95x90C(SO2R1)xe2x80x94, xe2x95x90C(S(O)R1)xe2x80x94, xe2x95x90C(C(O)R1)xe2x80x94, xe2x95x90C(C(O)H)xe2x80x94, xe2x95x90C(SR1a)xe2x80x94, xe2x95x90C(OR1a)xe2x80x94 or xe2x95x90C(NHR1a)xe2x80x94,
xe2x80x83wherein R1 is selected from the class consisting of:
(A) xe2x80x94R100a, which is:
xe2x80x83branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogen atoms are optionally and independently replaced with:
(i) halogen,
(ii) oxo,
(iii) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl or heteroaryl group are optionally and independently replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR8, wherein R8 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR9R10, wherein R9 and R10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R9 and R10 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR11R12, wherein R11 and R12 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R11 and R12 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94Hxe2x80x94, or xe2x80x94NMexe2x80x94,
(h) a group of the formula xe2x80x94OR13, wherein R13 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR14, wherein R14 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) xe2x80x94CN, or
(k) an amidino group of the formula 
xe2x80x83wherein R15, R16 and R17 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R15, R16 and R17 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(l) halogen,
(m) a group of the formula xe2x80x94NHCONHalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,
(n) a group of the formula xe2x80x94NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,
(iv) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(v) xe2x80x94CN,
(vi) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(vii) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety contains 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(viii) a group of the formula xe2x80x94SR22, wherein R22 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe and xe2x80x94Me2,
(ix) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) straight or branched alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2,
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or
(e) a group of the formula xe2x80x94(CH2)nCONHR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
(x) a quaternary group of the formula 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x80x94 is pharmaceutically acceptable counter ion,
(xi) a saturated, or partially unsaturated heterocyclic group consisting of 3 to 7 ring atoms selected from N, O, C and S, including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally mono- or polysubstituted with oxo, and
(xii) a cycloalkyl group of 3 to 7 carbon atoms,
(B) branched or unbranched carboxylic acid groups of 3 to 6 carbon atoms,
(C) branched or unbranched phosphonic acid groups of 2 to 6 carbon atoms,
(D) branched or unbranched sulfonic acid groups of 2 to 6 carbon atoms,
(E) amidino groups of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(F) guanidino groups of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6, and R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more hydrogen atoms of said aryl or heteroaryl group are optionally and independently replaced with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR36, wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR37R38, wherein R37 and R38 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR39R40, wherein R39 and R40 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R40 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(viii) a group of the formula xe2x80x94OR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(x) xe2x80x94CN, or
(xi) an amidino group of the formula 
xe2x80x83wherein R43, R44 and R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) groups of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, phenyl which is optionally mono- or polysubstituted with halogen, or R100a, wherein R100a is as hereinbefore defined,
(I) saturated or unsaturated heterocyclic groups consisting of 3 to 7 ring atoms selected from N, O, C and S, or bicyclic heterocyclic groups consisting of 8 to 11 atoms selected from N, O, C and S, including but not limited to imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally mono- or poly-substituted with moieties independently selected from the class consisting of:
(i) oxo,
(ii) xe2x80x94OR101, wherein R101 is:
(a) a hydrogen atom,
(b) alkyl of 1 to7 carbons, wherein any hydrogen atom of said alkyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR110 (wherein R110 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(c) acyl of 1 to 7 carbons, wherein any hydrogen atom of said acyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR111 (wherein R111 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(d) xe2x80x94CONR102R103, wherein R102 and R103 are each independently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R102 and R103 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94Hxe2x80x94, or xe2x80x94NMexe2x80x94, or
(e) xe2x80x94COOR104, wherein R104 is alkyl of 1 to 7 atoms,
(iii) xe2x80x94CONR105R106, wherein R105 and R106 are each independently:
(a) a hydrogen atom,
(b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms,
(c) benzoyl,
(d) benzyl or
(e) phenyl, wherein said phenyl ring is optionally mono- or polysubstituted with xe2x80x94OR112, wherein R112 is alkyl of 1 to 6 carbon atoms,
xe2x80x83or, wherein R105 and R106 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, S(O)xe2x80x94, SO2xe2x80x94, xe2x80x94Hxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) xe2x80x94COOR107, wherein R107 is a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms,
(v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, wherein one or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) oxo,
(b) xe2x80x94OH,
(c) xe2x80x94OR113, wherein R113 is alkyl of 1 to 6 carbon atoms,
(d) xe2x80x94OCOCH3,
(e) xe2x80x94NH2,
(f) xe2x80x94NHMe,
(g) xe2x80x94NMe2,
(h) xe2x80x94CO2H, and
(i) xe2x80x94CO2 R114 wherein R114 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,
(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or more hydrogen atoms of said acyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) xe2x80x94OH,
(b) xe2x80x94OR115, wherein R115 is alkyl of 1 to 6 carbon atoms,
(c) xe2x80x94NH2,
(d) xe2x80x94NHMe,
(e) xe2x80x94NMe2,
(f) xe2x80x94NHCOMe,
(g) oxo,
(h) xe2x80x94CO2 R116, wherein R116 is alkyl of 1 to 3 carbon atoms,
(i) xe2x80x94CN,
(j) the halogen atoms,
(k) heterocycles selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, and
(l) aryl or heteroaryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
(vii) xe2x80x94SO2R108, wherein R108 is:
(a) aryl or heteroaryl which is selected from the group consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR117 (wherein R117 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR118 (wherein R118 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR119 (wherein R119 is hydrogen or alkyl of 1 to 6 carbon atoms),
(viii) xe2x80x94COR109, wherein R109 is:
(a) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR120 (wherein R120 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl is optionally substituted with one or more halogen, straight or branched alkyl of 1 to 6 carbons, or xe2x80x94OR121 (wherein R121 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR122 (wherein R122 is hydrogen or alkyl of 1 to 6 carbon atoms),
(ix) xe2x80x94CHO,
(x) the halogen atoms, and
(xi) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
(J) the halogen atoms, and
(K) xe2x80x94CN and,
xe2x80x83wherein R1a is R100a;
X is an oxygen or sulfur atom;
R3 is:
(A) a hydrogen atom, or
(B) branched or unbranched alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 5 carbon atoms wherein said alkyl or cycloalkyl group is optionally substituted with:
(i) a group of the formula xe2x80x94OR48, wherein R48 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms, or
(ii) a group of the formula xe2x80x94NR49R50, wherein R49 and R50 are each, independently, a hydrogen atom, alkyl of 1 to 2 carbon atoms, or acyl of 1 to2 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein, R55 is.
xe2x80x83aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more of the hydrogen atoms of said aryl or heteroaryl group is optionally and independently replaced with:
(A) R59a, which is aryl or heteroaryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein one or more of the hydrogen atoms of said aryl or heteroaryl group is optionally and independently replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- or polysubstituted with halogen or oxo,
(ii) a group of the formula xe2x80x94COOR60, wherein R60 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(iii) a group of the formula xe2x80x94NR61 R62, wherein R61 and R62 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R61 and R62 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(iv) a group of the formula xe2x80x94CONR63R64, wherein R63 and R64 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R63 and R64 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(v) a group of the formula xe2x80x94OR65, wherein R65 is a hydrogen atom, or an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(vi) a group of the formula xe2x80x94SR66, wherein R66 is a hydrogen atom, or an alkyl , fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(vii) xe2x80x94CN,
(viii) nitro, or
(ix) halogen,
(B) methyl, which is optionally mono- or polysubstituted with fluorine atoms and additionally is optionally monosubstituted with R59a,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- or polysubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94NR68R69, wherein R68 and R69 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R68 and R69 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R68 and R69 may additionally be the group R59a,
(F) a group of the formula xe2x80x94CONR70R71, wherein R70 and R71 are each, independently, a hydrogen atom, alkyl or fluoroalkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R70 and R71 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one of R70 and R71 may additionally be the group R59a,
(G) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R59a,
(H) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59a,
(I) a group of the formula xe2x80x94SR74, wherein R74 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59a,
(J) xe2x80x94CN,
(K) nitro, or
(L) halogen;
R5 is Cl or trifluoromethyl;
Z is xe2x95x90Nxe2x80x94 or xe2x95x90C(R6)xe2x80x94 wherein R6 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl or trifluoromethyl; and,
R7 is a hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, xe2x80x94CN, nitro or trifluoromethyl, with the condition that when Z is xe2x95x90Nxe2x80x94 or xe2x95x90C(H)xe2x80x94, R7 is chlorine, trifluoromethyl, xe2x80x94CN or nitro;
and pharmaceutically acceptable salts thereof.
More preferred are compounds of the formula I wherein:
A1 is xe2x95x90Nxe2x80x94 or xe2x95x90C(H)xe2x80x94;
A2 is xe2x95x90Nxe2x80x94, or xe2x95x90C(H)xe2x80x94;
D is xe2x95x90Nxe2x80x94, xe2x95x90C(R1)xe2x80x94, xe2x95x90C(H)xe2x80x94, xe2x95x90C(SO2R1)xe2x80x94, xe2x95x90C(C(O)H)xe2x80x94 or xe2x95x90C(C(O)R1)xe2x80x94, wherein R1 is selected from the class consisting of:
(A) xe2x80x94R100b, which is:
xe2x80x83branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogen atoms are optionally and independently replaced with:
(i) oxo,
(ii) phenyl, wherein one hydrogen atom of said phenyl group is optionally replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR8, wherein R8 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR9R10, wherein R9 and R10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R9 and R10 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR11R12, wherein R11 and R12 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R11 and R12 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(h) a group of the formula xe2x80x94OR13, wherein R13 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR14, wherein R14 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) xe2x80x94CN, or
(k) an amidino group of the formula 
xe2x80x83wherein R15, R16 and R17 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R15, R16 and R17 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(l) a group of the formula xe2x80x94NHCONHalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,
(m) a group of the formula xe2x80x94NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,
(iii) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(iv) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(v) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety contains 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(vi) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) straight or branched alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2,
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or
(e) a group of the formula xe2x80x94(CH2)nCONHR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
(vii) a quaternary group of the formula 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x80x94 is a pharmaceutically acceptable counter ion, or
(viii) a cycloalkyl group of 3 to 7 carbon atoms,
(B) branched or unbranched carboxylic acid groups of 3 to 6 carbon atoms,
(C) branched or unbranched phosphonic acid groups of 2 to 6 carbon atoms,
(D) branched or unbranched sulfonic acid groups of 2 to 6 carbon atoms,
(E) amidino groups of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(F) guanidino groups of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6, and R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) phenyl, wherein one or more hydrogen atoms of said phenyl group are optionally and independently replaced with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR36, wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR37R38, wherein R37 and R38 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR39R40, wherein R39 and R40 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R40 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(viii) a group of the formula xe2x80x94OR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(x) xe2x80x94CN, or
(xi) an amidino group of the formula 
xe2x80x83wherein R43, R44 and R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) groups of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, phenyl which is optionally mono- or polysubstituted with halogen, or R100b, wherein R100b is as hereinbefore defined,
(I) saturated or unsaturated heterocyclic groups selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally mono- or poly-substituted with moieties independently selected from the class consisting of:
(i) oxo,
(ii) xe2x80x94OR101, wherein R101 is:
(a) a hydrogen atom,
(b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of said alkyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR110 (wherein R110 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(c) acyl of 1 to 7 carbons, wherein any hydrogen atom of said acyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR111 (wherein R111 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(d) xe2x80x94CONR102R103, wherein R102 and R103 are each independently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R102 and R103 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94, or
(e) xe2x80x94COOR104, wherein R104 is alkyl of 1 to 7 atoms,
(iii) xe2x80x94CONR105R106, wherein R105 and R106 are each independently:
(a) a hydrogen atom,
(b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms,
(c) benzoyl,
(d) benzyl or
(e) phenyl, wherein said phenyl ring is optionally mono- or polysubstituted with xe2x80x94OR112, wherein R112 is alkyl of 1 to 6 carbon atoms,
xe2x80x83or, wherein R105 and R106 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) xe2x80x94COOR107, wherein R107 is a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms,
(v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, wherein one or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) oxo,
(b) xe2x80x94OH,
(c) xe2x80x94OR113, wherein R113 is alkyl of 1 to 6 carbon atoms,
(d) xe2x80x94OCOCH3,
(e) xe2x80x94NH2,
(f) xe2x80x94NHMe,
(g) xe2x80x94NMe2,
(h) xe2x80x94CO2H, and
(i) xe2x80x94CO2R114 wherein R114 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,
(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or more hydrogen atoms of said acyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) xe2x80x94OH,
(b) xe2x80x94OR115, wherein R115 is alkyl of 1 to 6 carbon atoms,
(c) xe2x80x94NH2,
(d) xe2x80x94NHMe,
(e) xe2x80x94NMe2,
(f) xe2x80x94NHCOMe,
(g) oxo,
(h) xe2x80x94CO2R116, wherein R116 is alkyl of 1 to 3 carbon atoms,
(i) xe2x80x94CN,
(j) the halogen atoms,
(k) heterocycles selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, and
(l) aryl or heteroaryl selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
(vii) xe2x80x94SO2R108, wherein R108 is:
(a) aryl or heteroaryl which is selected from the group consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR117 (wherein R117 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclic group is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR118 (wherein R118 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR119 (wherein R119 is hydrogen or alkyl of 1 to 6 carbon atoms),
(viii) xe2x80x94COR109, wherein R109 is:
(a) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR120 (wherein R120 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of imidazolinyl, imidazolidinyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepinyl, tetrahydropyranyl, tetrahydrofuranyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl, wherein said heterocyclyl is optionally substituted with one or more halogen, straight or branched alkyl of 1 to 6 carbons, or xe2x80x94OR121 (wherein R121 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR122 (wherein R122 is hydrogen or alkyl of 1 to 6 carbon atoms),
(ix) xe2x80x94CHO,
(x) the halogen atoms, and
(xi) aryl or heteroaryl which is selected from the class consisting of phenyl, naphthyl, indolyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, triazinyl, indolyzinyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzthiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, quinolizinyl, cinnolinyl, pthalaninyl, quinoxalinyl, napthyridinyl, pteridinyl and quinazolinyl,
(J) the halogen atoms, and
(K) xe2x80x94CN;
X is an oxygen atom;
R3 is branched or unbranched alkyl of 1 to 3 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein,
R55 is:
xe2x80x83aryl or heteroaryl which is selected from the class consisting of phenyl, pyridyl, and pyrimidinyl, wherein one or more of the hydrogen atoms of said aryl or heteroaryl group is optionally and independently replaced with:
(A) R59b, which is aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, and thiazolyl, wherein one of the hydrogen atoms of said aryl or heteroaryl group is optionally replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- or polysubstituted with halogen or oxo,
(ii) xe2x80x94CN,
(iii) nitro, or
(iv) halogen,
(B) methyl, which is optionally trisubstituted with fluorine atoms or is optionally monosubstituted with R59b,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally monosubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms or R59b,
(F) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl, fluoroalkyl or acyl group of 1 to 7 carbon atoms, or R59b,
(G) xe2x80x94CN,
(H) nitro, or
(I) halogen;
R5 is Cl;
Z is xe2x95x90C(H)xe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof.
Even more preferred are compounds of the formula I, wherein:
A1 is xe2x95x90Nxe2x80x94;
A2 is xe2x95x90C(H)xe2x80x94;
D is xe2x95x90C(R1)xe2x80x94, xe2x95x90C(H)xe2x80x94, xe2x95x90C(SO2R1)xe2x80x94, xe2x95x90C(C(O)H)xe2x80x94 or xe2x95x90C(C(O)R1)xe2x80x94, wherein R1 is selected from the class consisting of:
(A) xe2x80x94R100c, which is:
xe2x80x83branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogen atoms are optionally and independently replaced with:
(i) oxo,
(ii) phenyl, wherein one hydrogen atom of said phenyl group is optionally replaced with:
(a) alkyl of 1 to 3 carbon atoms,
(b) xe2x80x94COOH,
(c) xe2x80x94SO2OH,
(d) xe2x80x94PO(OH)2,
(e) a group of the formula xe2x80x94COOR8, wherein R8 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(f) a group of the formula xe2x80x94NR9R10, wherein R9 and R10 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R9 and R10 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(g) a group of the formula xe2x80x94CONR11R12, wherein R11 and R12 are each independently a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R11 and R12 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(h) a group of the formula xe2x80x94OR13, wherein R13 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(i) a group of the formula xe2x80x94SR14, wherein R14 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(j) xe2x80x94CN, or
(k) an amidino group of the formula 
xe2x80x83wherein R15, R16 and R17 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms and wherein two of R15, R16 and R17 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(l) a group of the formula xe2x80x94NHCONHalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,
(m) a group of the formula xe2x80x94NHCOOalkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms,
(iii) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(iv) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(v) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety contains 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(vi) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) straight or branched alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety is 1 to6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2,
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or
(e) a group of the formula xe2x80x94(CH2)nCONHR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
(vii) a quaternary group of the formula 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x80x94 is a pharmaceutically acceptable counter ion, or
(viii) a cycloalkyl group of 3 to 7 carbon atoms,
(B) branched or unbranched carboxylic acid groups of 3 to 6 carbon atoms,
(C) branched or unbranched phosphonic acid groups of 2 to 6 carbon atoms,
(D) branched or unbranched sulfonic acid groups of 2 to 6 carbon atoms,
(E) amidino groups of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(F) guanidino groups of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6, and R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) phenyl, wherein one or more hydrogen atoms of said phenyl group are optionally and independently replaced with:
(i) alkyl of 1 to 3 carbon atoms,
(ii) xe2x80x94COOH,
(iii) xe2x80x94SO2OH,
(iv) xe2x80x94PO(OH)2,
(v) a group of the formula xe2x80x94COOR36, wherein R36 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(vi) a group of the formula xe2x80x94NR37R38, wherein R37 and R38 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or acyl of 1 to 7 carbon atoms, or wherein R37 and R38 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring,
(vii) a group of the formula xe2x80x94CONR39R40, wherein R39 and R40 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R39 and R40 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(viii) a group of the formula xe2x80x94OR41, wherein R41 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(ix) a group of the formula xe2x80x94SR42, wherein R42 is a hydrogen atom, or an alkyl or acyl group of 1 to 7 carbon atoms,
(x) xe2x80x94CN, or
(xi) an amidino group of the formula 
xe2x80x83wherein R43, R44 and R45 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R43, R44 and R45 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(H) groups of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, phenyl which is optionally monosubstituted with halogen, or R100c, wherein R100c is as hereinbefore defined,
(I) saturated or unsaturated heterocyclic groups selected from the class consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclic groups are optionally mono- or poly-substituted with moieties independently selected from the class consisting of:
(i) oxo,
(ii) xe2x80x94OR101, wherein R101 is:
(a) a hydrogen atom,
(b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of said alkyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR110 (wherein R110 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(c) acyl of 1 to 7 carbons, wherein any hydrogen atom of said acyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR111 (wherein R111 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(d) xe2x80x94CONR102R103, wherein R102 and R103 are each independently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R102 and R103 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94, or
(e) xe2x80x94COOR104, wherein R104 is alkyl of 1 to 7 atoms,
(iii) xe2x80x94CONR105R106, wherein R105 and R106 are each independently:
(a) a hydrogen atom,
(b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms,
(c) benzoyl,
(d) benzyl or
(e) phenyl, wherein said phenyl ring is optionally mono- or polysubstituted with xe2x80x94OR112, wherein R112 is alkyl of 1 to 6 carbon atoms,
xe2x80x83or, wherein R105 and R106 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) xe2x80x94COOR107, wherein R107 is a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms,
(v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, wherein one or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) oxo,
(b) xe2x80x94OH,
(c) xe2x80x94OR113, wherein R113 is alkyl of 1 to 6 carbon atoms,
(d) xe2x80x94OCOCH3,
(e) xe2x80x94NH2,
(f) xe2x80x94NHMe,
(g) xe2x80x94NMe2,
(h) xe2x80x94CO2H, and
(i) xe2x80x94CO2 R114 wherein R114 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,
(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or more hydrogen atoms of said acyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) xe2x80x94OH,
(b) xe2x80x94OR 115, wherein R115 is alkyl of 1 to 6 carbon atoms,
(c) xe2x80x94NH2,
(d) xe2x80x94NHMe,
(e) xe2x80x94NMe2,
(f) xe2x80x94NHCOMe,
(g) oxo,
(h) xe2x80x94CO2 R116, wherein R116 is alkyl of 1 to 3 carbon atoms,
(i) xe2x80x94CN,
(j) the halogen atoms,
(k) heterocycles selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and
(l) aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,
(vii) xe2x80x94SO2R108, wherein R108 is:
(a) aryl or heteroaryl which is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl thiazolyl and pyrazolyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR117 (wherein R117 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclic group is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR118 (wherein R118 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR119 (wherein R119 is hydrogen or alkyl of 1 to 6 carbon atoms),
(viii) xe2x80x94COR109, wherein R109 is:
(a) aryl or heteroaryl which is selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl and pyrazolyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to6 carbons, and xe2x80x94OR120 (wherein R120 is hydrogen or alkyl of 1 to6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclyl is optionally substituted with one or more halogen, straight or branched alkyl of 1 to 6 carbons, or xe2x80x94OR121 (wherein R121 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR122 (wherein R122 is hydrogen or alkyl of 1 to 6 carbon atoms),
(ix) xe2x80x94CHO,
(x) the halogen atoms, and
(xi) aryl or heteroaryl which is selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and imidazolyl,
(J) the halogen atoms, and
(K) xe2x80x94CN;
X is an oxygen atom;
R3 is branched or unbranched alkyl of 1 to 3 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein,
R55 is:
xe2x80x83phenyl, which is optionally substituted at the 4-position with:
(A) R59c, which is aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl, wherein one of the hydrogen atoms of said aryl or heteroaryl group is optionally replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- or polysubstituted with halogen or oxo,
(ii) xe2x80x94CN,
(iii) nitro, or
(iv) halogen,
(B) methyl,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally monosubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, or cycloalkyl of 3 to 5 carbon atoms,
(F) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl, or fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(G) xe2x80x94CN,
(H) nitro, or
(I) halogen;
R5 is Cl;
Z is xe2x95x90C(H)xe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof.
Further preferred are compounds of the formula I wherein:
A1 is xe2x95x90Nxe2x80x94;
A2 is xe2x95x90C(H)xe2x80x94;
D is xe2x95x90C(H)xe2x80x94, xe2x95x90C(SO2R1)xe2x80x94 or xe2x95x90C(C(O)R1)xe2x80x94, wherein R1 is selected from the class consisting of:
xe2x80x94R100d, which is:
xe2x80x83branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogen atoms are optionally and independently replaced with:
(i) oxo,
(ii) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(iii) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety contains 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(v) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) straight or branched alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2,
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or
(e) a group of the formula xe2x80x94(CH2)nCONHR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
(vi) a quaternary group of the formula 
xe2x80x83wherein R26, R27 and R28 are each, independently, a branched or unbranched alkyl group of 1 to 7 carbon atoms and Qxe2x80x94 is a pharmaceutically acceptable counter ion, or
(vii) a cycloalkyl group of 3 to 7 carbon atoms,
(B) branched or unbranched carboxylic acid groups of 3 to 6 carbon atoms,
(C) branched or unbranched phosphonic acid groups of 2 to 6 carbon atoms,
(D) branched or unbranched sulfonic acid groups of 2 to 6 carbon atoms,
(E) amidino groups of the formula 
xe2x80x83wherein r is 2, 3, 4, 5 or 6, and R29, R30 and R31 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R29, R30 and R31 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(F) guanidino groups of the formula 
xe2x80x83wherein s is 2, 3, 4, 5 or 6, and R32, R33, R34 and R35 are each, independently, a hydrogen atom or alkyl of 1 to 3 carbon atoms, and wherein two of R32, R33, R34 and R35 may additionally constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom(s) between them form a heterocyclic ring,
(G) groups of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, phenyl which is optionally monosubstituted with halogen, or R100d, wherein R100d is as hereinbefore defined,
(H) saturated or unsaturated heterocyclic groups selected from the class consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclic groups are optionally mono- or poly-substituted with moieties independently selected from the class consisting of:
(i) oxo,
(ii) xe2x80x94OR101, wherein R101 is:
(a) a hydrogen atom,
(b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of said alkyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR110 (wherein R110 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(c) acyl of 1 to 7 carbons, wherein any hydrogen atom of said acyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR111 (wherein R111 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(d) xe2x80x94CONR102R103, wherein R102 and R103 are each independently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R102 and R103 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94, or
(e) xe2x80x94COOR104, wherein R104 is alkyl of 1 to 7 atoms,
(iii) xe2x80x94CONR105R106, wherein R105 and R106 are each independently:
(a) a hydrogen atom,
(b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms,
(c) benzoyl,
(d) benzyl or
(e) phenyl, wherein said phenyl ring is optionally mono- or polysubstituted with xe2x80x94OR112, wherein R112 is alkyl of 1 to 6 carbon atoms,
xe2x80x83or, wherein R105 and R106 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) xe2x80x94COOR107, wherein R107 is a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms,
(v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, wherein one or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) oxo,
(b) xe2x80x94OH,
(c) xe2x80x94OR113, wherein R113 is alkyl of 1 to 6 carbon atoms,
(d) xe2x80x94OCOCH3,
(e) xe2x80x94NH2,
(f) xe2x80x94NHMe,
(g) xe2x80x94NMe2,
(h) xe2x80x94CO2H, and
(i) xe2x80x94CO2 R114 wherein R114 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,
(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or more hydrogen atoms of said acyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) xe2x80x94OH,
(b) xe2x80x94OR115, wherein R115 is alkyl of 1 to 6 carbon atoms,
(c) xe2x80x94NH2,
(d) xe2x80x94NHMe,
(e) xe2x80x94NMe2,
(f) xe2x80x94NHCOMe,
(g) oxo,
(h) xe2x80x94CO2 R116, wherein R116 is alkyl of 1 to 3 carbon atoms,
(i) xe2x80x94CN,
(j) the halogen atoms,
(k) heterocycles selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and
(l) aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,
(vii) xe2x80x94SO2R108, wherein R108 is:
(a) aryl or heteroaryl which is selected from the group consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl thiazolyl and pyrazolyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to6 carbons, and xe2x80x94OR117 (wherein R117 is hydrogen or alkyl of 1 to6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclic group is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR118 (wherein R118 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR119 (wherein R119 is hydrogen or alkyl of 1 to 6 carbon atoms),
(viii) xe2x80x94COR109, wherein R109 is:
(a) aryl or heteroaryl which is selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl and pyrazolyl, wherein said aryl or heteroaryl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to6 carbons, and xe2x80x94OR120 (wherein R120 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclyl is optionally substituted with one or more halogen, straight or branched alkyl of 1 to 6 carbons, or xe2x80x94OR121 (wherein R121 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR122 (wherein R122 is hydrogen or alkyl of 1 to 6 carbon atoms),
(ix) xe2x80x94CHO,
(x) the halogen atoms, and
(xi) aryl or heteroaryl which is selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl and imidazolyl, and
(I) the halogen atoms,
X is an oxygen atom;
R3 is branched or unbranched alkyl of 1 to 3 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein,
R55 is:
xe2x80x83phenyl, which is optionally substituted at the 4-position with:
(A) R59d, which is aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl, wherein one of the hydrogen atoms of said aryl or heteroaryl group is optionally replaced with:
(i) branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally mono- or polysubstituted with halogen or oxo,
(ii) xe2x80x94CN,
(iii) nitro, or
(iv) halogen,
(B) methyl,
(C) branched or unbranched alkyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, which alkyl or cycloakyl group is optionally monosubstituted with halogen or oxo,
(D) a group of the formula xe2x80x94COOR67, wherein R67 is straight or branched alkyl of 1 to 5 carbon atoms or cycloalkyl of 3 to 5 carbon atoms,
(E) a group of the formula xe2x80x94COR72, wherein R72 is a hydrogen atom, straight or branched alkyl of 1 to 5 carbon atoms, or cycloalkyl of 3 to 5 carbon atoms,
(F) a group of the formula xe2x80x94OR73, wherein R73 is a hydrogen atom, an alkyl, or fluoroalkyl or acyl group of 1 to 7 carbon atoms,
(G) xe2x80x94CN,
(H) nitro, or
(I) halogen;
R5 is Cl;
Z is xe2x95x90C(H)xe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof.
Especially preferred are compounds of the formula I wherein:
A1 is xe2x95x90Nxe2x80x94;
A2 is xe2x95x90C(H)xe2x80x94;
D is xe2x95x90C(SO2R1)xe2x80x94 or xe2x95x90C(C(O)R1)xe2x80x94, wherein R1 is selected from the class consisting of:
(A) xe2x80x94R100e, which is:
xe2x80x83branched or unbranched alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl or cycloalkenyl of 3 to 6 carbon atoms, in which alkyl, alkenyl, cycloalkyl or cycloalkenyl group one or more hydrogen atoms are optionally and independently replaced with:
(i) oxo,
(ii) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(iii) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms, wherein one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety contains 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2, or
(v) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) straight or branched alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein said one or more hydrogen atoms of said alkyl or acyl group are optionally replaced with a group independently selected from the class consisting of xe2x80x94OH, xe2x80x94Oalkyl (wherein the alkyl moiety is 1 to 6 carbon atoms), xe2x80x94H2, xe2x80x94NHMe and xe2x80x94NMe2,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2,
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or
(e) a group of the formula xe2x80x94(CH2)nCONHR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms,
(B) groups of the formula xe2x80x94NR46R47, wherein R46 and R47 are each independently a hydrogen atom, phenyl which is optionally monosubstituted with halogen, or R100e, wherein R100e is as hereinbefore defined, and
(C) saturated or unsaturated heterocyclic groups selected from the class consisting of pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclic groups are optionally mono- or poly-substituted with moieties independently selected from the class consisting of:
(i) oxo,
(ii) xe2x80x94OR101, wherein R101 is:
(a) a hydrogen atom,
(b) alkyl of 1 to 7 carbons, wherein any hydrogen atom of said alkyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR110 (wherein R110 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(c) acyl of 1 to 7 carbons, wherein any hydrogen atom of said acyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR111 (wherein R111 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(d) xe2x80x94CONR102R103, wherein R102 and R103 are each independently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R102 and R103 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94, or
(e) xe2x80x94COOR104, wherein R104 is alkyl of 1 to 7 atoms,
(iii) xe2x80x94CONR105R106, wherein R105 and R106 are each independently:
(a) a hydrogen atom, or
(b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms,
xe2x80x83or, wherein R105 and R106 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) xe2x80x94COOR107, wherein R107 is a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms,
(v) straight or branched alkyl of 1 to 7 carbon atoms, alkenyl or alkynyl of 2 to 7 carbon atoms, or cycloalkyl of 3 to 7 carbons, wherein one or more hydrogen atoms of said alkyl, alkenyl, alkynyl or cycloalkyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) oxo,
(b) xe2x80x94OH,
(c) xe2x80x94OR113, wherein R113 is alkyl of 1 to 6 carbon atoms,
(d) xe2x80x94OCOCH3,
(e) xe2x80x94NH2,
(f) xe2x80x94NHMe,
(g) xe2x80x94NMe2,
(h) xe2x80x94CO2H, and
(i) xe2x80x94CO2 R114 wherein R114 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,
(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or more hydrogen atoms of said acyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) xe2x80x94OH,
(b) xe2x80x94OR115, wherein R115 is alkyl of 1 to 6 carbon atoms,
(c) xe2x80x94NH2,
(d) xe2x80x94NHMe,
(e) xe2x80x94NMe2,
(f) xe2x80x94NHCOMe,
(g) oxo,
(h) xe2x80x94CO2 R116, wherein R116 is alkyl of 1 to 3 carbon atoms,
(i) xe2x80x94CN,
(j) the halogen atoms,
(k) heterocycles selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and
(l) aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,
(vii) xe2x80x94SO2R108, wherein R108 is:
(a) phenyl, wherein said phenyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR117 (wherein R117 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclic group is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR118 (wherein R118 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR119 (wherein R119 is hydrogen or alkyl of 1 to 6 carbon atoms),
(viii) xe2x80x94COR109, wherein R109 is:
(a) phenyl, wherein said phenyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR120 (wherein R120 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclyl is optionally substituted with one or more halogen, straight or branched alkyl of 1 to 6 carbons, or xe2x80x94OR121 (wherein R121 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one or more moieties selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR122 (wherein R122 is hydrogen or alkyl of 1 to 6 carbon atoms), and
(ix) xe2x80x94CHO;
X is an oxygen atom;
R3 is branched or unbranched alkyl of 1 to 3 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein,
R55 is:
xe2x80x83phenyl, which is optionally substituted at the 4-position with:
(A) R59e, which is aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl, wherein one of the hydrogen atoms of said aryl or heteroaryl group is optionally replaced with:
(i) methyl,
(ii) xe2x80x94CN,
(iii) nitro, or
(iv) halogen,
(B) methyl,
(C) xe2x80x94CN,
(D) nitro, or
(E) halogen;
R5 is Cl;
Z is xe2x95x90C(H)xe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof.
More especially preferred are compounds of the formula I wherein:
A1 is xe2x95x90Nxe2x80x94;
A2 is xe2x95x90C(H)xe2x80x94;
D is xe2x95x90C(SO2R1)xe2x80x94 or xe2x95x90C(C(O)R1)xe2x80x94, wherein R1 is selected from the class consisting of:
(A) xe2x80x94R100e, which is:
xe2x80x83branched or unbranched alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, in which alkyl, or cycloalkyl group one to three hydrogen atoms are optionally and independently replaced with:
(i) oxo,
(ii) a group of the formula xe2x80x94COOR18, wherein R18 is straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 6 carbon atoms,
(iii) a group of the formula xe2x80x94CONR19R20, wherein R19 and R20 are each, independently, a hydrogen atom, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, or wherein R19 and R20 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) a group of the formula xe2x80x94OR21, wherein R21 is a hydrogen atom, or a straight or branched alkyl or acyl group of 1 to 7 carbon atoms, or
(v) a group of the formula xe2x80x94NR23R24, wherein R23 and R24 are each, independently,
(a) a hydrogen atom,
(b) straight or branched alkyl or acyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbon atoms,
(c) a group of the formula xe2x80x94(CH2)mCOOH, wherein m is 0, 1 or 2,
(d) a group of the formula xe2x80x94(CH2)nCOOR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, or
(e) a group of the formula xe2x80x94(CH2)nCONHR25, wherein n is 0, 1 or 2, and wherein R25 is straight or branched alkyl of 1 to 6 carbon atoms, and
(B) saturated heterocyclic groups selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclic groups are optionally mono- or di-substituted with moieties independently selected from the class consisting of:
(i) oxo,
(ii) xe2x80x94OR101, wherein R101 is:
(a) a hydrogen atom,
(b) alkyl of 1 to 7 carbons, wherein one hydrogen atom of said alkyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR110 (wherein R110 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(c) acyl of 1 to 7 carbons, wherein one hydrogen atom of said acyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR111 (wherein R111 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(d) xe2x80x94CONR102R103, wherein R102 and R103 are each independently a hydrogen atom or alkyl of 1 to 7 atoms, or wherein R102 and R103 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94, or
(e) xe2x80x94COOR104, wherein R104 is alkyl of 1 to 7 atoms,
(iii) xe2x80x94CONR105R106, wherein R105 and R106 are each independently:
(a) a hydrogen atom, or
(b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms, wherein said alkyl or cycloalkyl group is optionally monosubstituted with xe2x80x94OH, xe2x80x94OR123 (wherein R123 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94NMe2, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, or, wherein R105 and R106 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) xe2x80x94COOR107, wherein R107 is a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms,
(v) straight or branched alkyl of 1 to 7 carbon atoms or cycloalkyl of 3 to 7 carbons, wherein one to three hydrogen atoms of said alkyl or cycloalkyl group is optionally replaced with a moiety independently selected from the class consisting of:
(a) oxo,
(b) xe2x80x94OH,
(c) xe2x80x94OR113, wherein R113 is alkyl of 1 to 6 carbon atoms,
(d) xe2x80x94OCOCH3,
(e) xe2x80x94NH2,
(f) xe2x80x94NHMe,
(g) xe2x80x94NMe2,
(h) xe2x80x94CO2H, and
(i) xe2x80x94CO2 R114 wherein R114 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,
(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or two hydrogen atoms of said acyl group is optionally replaced with a moiety selected from the class consisting of:
(a) xe2x80x94OH,
(b) xe2x80x94OR115, wherein R115 is alkyl of 1 to 6 carbon atoms,
(c) xe2x80x94NH2,
(d) xe2x80x94NHMe,
(e) xe2x80x94NMe2;
(f) xe2x80x94NHCOMe,
(g) oxo,
(h) xe2x80x94CO2 R116, wherein R116 is alkyl of 1 to 3 carbon atoms,
(i) xe2x80x94CN,
(j) the halogen atoms,
(k) heterocycles selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and
(l) aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,
(vii) xe2x80x94SO2R108, wherein R108 is:
(a) phenyl, wherein said phenyl moiety is optionally substituted with one moiety selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR117 (wherein R117 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclic group is optionally substituted with one moiety selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR118 (wherein R118 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one moiety selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR119 (wherein R119 is hydrogen or alkyl of 1 to 6 carbon atoms),
(viii) xe2x80x94COR109, wherein R109 is:
(a) phenyl, wherein said phenyl moiety is optionally substituted with one moiety selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR120 (wherein R120 is hydrogen or alkyl of 1 to 6 carbon atoms),
(b) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, wherein said heterocyclyl is optionally substituted with one halogen, straight or branched alkyl of 1 to 6 carbons, or xe2x80x94OR121 (wherein R121 is hydrogen or alkyl of 1 to 6 carbon atoms), or
(c) straight or branched alkyl of 1 to 7 atoms, wherein said alkyl moiety is optionally substituted with one moiety selected from the class consisting of the halogen atoms, straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR122 (wherein R122 is hydrogen or alkyl of 1 to6 carbon atoms), and
(ix) xe2x80x94CHO;
X is an oxygen atom;
R3 is branched or unbranched alkyl of 1 to 3 carbon atoms;
R4 is a group of the formula xe2x80x94CH2R55, wherein,
R55 is:
xe2x80x83phenyl, which is optionally substituted at the 4-position with:
(A) R59e, which is aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl and furyl, wherein one of the hydrogen atoms of said aryl or heteroaryl group is optionally replaced with:
(i) methyl,
(ii) xe2x80x94CN,
(iii) nitro, or
(iv) halogen,
(B) methyl,
(C) xe2x80x94CN,
(D) nitro, or
(E) halogen;
R5 is Cl;
Z is xe2x95x90C(H)xe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof.
Penultimately preferred are compounds of formula I wherein:
A1 is xe2x95x90Nxe2x80x94;
A2 is xe2x95x90C(H)xe2x80x94;
D is xe2x95x90C(SO2R1)xe2x80x94, wherein R1 is selected from the class consisting of:
(A) methyl, and
(B) saturated heterocyclic groups selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein said heterocyclic groups are optionally mono- or di-substituted with moieties independently selected from the class consisting of:
(i) oxo,
(ii) xe2x80x94OR101, wherein R101 is:
(a) a hydrogen atom,
(b) alkyl of 1 to 7 carbons, wherein one hydrogen atom of said alkyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR110 (wherein R110 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2, or
(c) acyl of 1 to 7 carbons, wherein one hydrogen atom of said acyl group is optionally replaced with xe2x80x94OH, xe2x80x94OR111 (wherein R111 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe or xe2x80x94NMe2,
(iii) xe2x80x94CONR105R106, wherein R105 and R106 are each independently:
(a) a hydrogen atom, or
(b) straight or branched alkyl of 1 to 7 atoms or cycloalkyl of 3 to 7 atoms, wherein said alkyl or cycloalkyl group is optionally monosubstituted with xe2x80x94OH, xe2x80x94OR123 (wherein R123 is an alkyl moiety of 1 to 6 carbon atoms), xe2x80x94NH2, xe2x80x94NHMe, xe2x80x94NMe2, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, or, wherein R105 and R106 constitute a saturated hydrocarbon bridge of 3 to 5 carbon atoms which together with the nitrogen atom between them form a heterocyclic ring, and wherein one carbon atom in said hydrocarbon bridge is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94NMexe2x80x94,
(iv) xe2x80x94COOR107, wherein R107 is a hydrogen atom, or straight or branched alkyl of 1 to 7 carbon atoms,
(v) straight or branched alkyl of 1 to 7 carbon atoms wherein one or two hydrogen atoms of said alkyl group are optionally replaced with moieties independently selected from the class consisting of:
(a) oxo,
(b) xe2x80x94OH,
(c) xe2x80x94OR113, wherein R113 is alkyl of 1 to 6 carbon atoms,
(d) xe2x80x94OCOCH3,
(e) xe2x80x94NH2,
(f) xe2x80x94NHMe,
(g) xe2x80x94NMe2,
(h) xe2x80x94CO2H, and
(i) xe2x80x94CO2 R114 wherein R114 is alkyl of 1 to 3 carbon atoms, or cycloalkyl of 3 to 7 carbons,
(vi) acyl of 1 to 7 carbon atoms, which may be straight, branched or cyclic, and wherein one or two hydrogen atoms of said acyl group is optionally replaced with a moiety selected from the class consisting of:
(a) xe2x80x94OH,
(b) xe2x80x94OR115, wherein R115 is alkyl of 1 to 6 carbon atoms,
(c) xe2x80x94NH2,
(d) xe2x80x94NHMe,
(e) xe2x80x94NMe2,
(f) xe2x80x94NHCOMe,
(g) oxo,
(h) xe2x80x94CO2 R116, wherein R116 is alkyl of 1 to 3 carbon atoms,
(i) xe2x80x94CN,
(j) the halogen atoms,
(k) heterocycles selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl, and
(l) aryl or heteroaryl selected from the class consisting of phenyl, thiophenyl, pyridyl, pyrimidinyl, furyl, pyrrolyl and oxazolyl,
(vii) xe2x80x94SO2R108, wherein R108 is:
(a) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein said heterocyclic group is optionally substituted with one moiety selected from the class consisting of straight or branched alkyl of 1 to 6 carbons, and xe2x80x94OR118 (wherein R118 is hydrogen or alkyl of 1 to 6 carbon atoms),
(viii) xe2x80x94COR109, wherein R109 is:
(a) a heterocyclic group selected from the class consisting of pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein said heterocyclyl is optionally substituted with one halogen, straight or branched alkyl of 1 to 6 carbons, or xe2x80x94OR121 (wherein R121 is hydrogen or alkyl of 1 to 6 carbon atoms), and
(ix) xe2x80x94CHO;
X is an oxygen atom;
R3 is methyl;
R4 is a group of the formula xe2x80x94CH2R55, wherein,
R55 is:
xe2x80x83phenyl, which is optionally substituted at the 4-position with:
(A) R59e, which is aryl or heteroaryl selected from the class consisting of phenyl, pyridyl, and pyrimidinyl
(B) xe2x80x94CN,
(B) nitro, or
(C) halogen;
R5 is Cl;
Z is xe2x95x90C(H)xe2x80x94; and,
R7 is Cl;
and pharmaceutically acceptable salts thereof.
It will be appreciated that the compounds of the formula I have at least one chiral center. Ultimately preferred are those compounds of formula I with the absolute stereochemistry depicted below in formula II. 
Also preferred are the following specific compounds: 
and their pharmaceutically acceptable salts.
Additionally it will be noted that certain compounds are useful as intermediates in the synthesis of the above compounds of the invention. In particular, compounds of the formula 
wherein,
R1 is selected from the class consisting of:
(A) hydrogen,
(B) the halogen atoms, and
(C) SO2xe2x88x92M+, wherein M+ is
(i) Li+,
(ii) Na+,
(iii) K+, or
(iv) MgX+, wherein X is a halogen; and
R2 is selected from the class consisting of:
(A) the halogen atoms,
(B) aryl, selected from the class of
(i) phenyl,
(ii) pyridyl, and
(iii) pyrimidyl, and
(C) CN.
Compounds of the invention may be prepared by the general methods described below. Typically, reaction progress may be monitored by thin layer chromatography (TLC) if desired. If desired, intermediates and products may be purified by chromatography on silica gel and/or recrystallization, and characterized by one or more of the following techniques: NMR, mass spectroscopy and melting point. Starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature. Intermediates used in the preparation of the compounds of formula I may be prepared by the method described below and outlined in Scheme I. 
An appropriate amino acid (III) is dissolved in aqueous base (such as, for example, NaOH, KOH, Na2CO3, NaHCO3, K2CCO3 or KHCO3) and warmed to between about 20 and 90xc2x0 C. An appropriate isocyanate (IV) is added to this mixture and the resulting solution is stirred until the reaction essentially reaches completion. Upon cooling, the mixture is acidified and the resulting ureidoacetic acid is isolated by filtration or by extraction into organic solvent. Removal of solvent produces the intermediate ureidoacetic acid. In the manner reported by Sauli (U.S. Pat. No. 4,099,008), the intermediate ureidoacetic acid is cyclized by heating in the presence of a catalytic amount of acid (such as, for example, sulfuric acid, methanesulfonic acid, benzenesulfonic acid or hydrochloric acid) in an organic or aqueous solvent, to produce the desired hydantoin (V). Workup consists of collection of the hydantoin by filtration and purification by, for example, silica gel chromatography or recrystallization.
If the thiocarbonyl VII is desired, several reagents are known in the literature which will convert carbonyls to thiocarbonyls. A typical sequence involves heating the substrate with a reagent such as P2S3 in a high boiling solvent such as tetralin for between 1 and 48 h. Isolation of the product follows relatively standard conditions such as the dilution of the mixture into an organic solvent such as EtOAc and washing this mixture with water and saturated aqueous NaCl followed by drying and concentration. Purification is accomplished by silica gel chromatography or recrystallization, to afford VI.
Intermediate VI can be selectively hydrolyzed to the desired monothiocarbonyl compound depending on the choice of conditions. In general the thiocarbonyl at the 4-position of the ring is more susceptible to nucleophilic conditions. It can be converted to the 4-oxo-species (VII) by treatment with aqueous ethanolamine followed by acid hydrolysis. Purification is easily performed by silica gel chromatography or recrystallization.
Alternatively, the methyl or ethyl ester of III may be reacted with an aryl thioisocyanate (IV: xe2x80x94NCS instead of xe2x80x94CO) in a suitable solvent, such as 1,4-dioxane, under an inert atmosphere at about 50-100xc2x0 C. for about 1-24 h to provide VII.
If one uses the racemic III or ester of III, the product (V or VII) is racemic at the asymmetric carbon. By starting with a single enantiomer of III or ester of III, one obtains the single enantiomer of V or VII.
Compounds of formula I where A1xe2x95x90N, A2xe2x95x90CH and Dxe2x95x90CH may be synthesized as illustrated in Scheme II and described below. 
Azide VIII is added to a solution of PPh3 in a suitable solvent such as toluene, under inert atmosphere and allowed to stir at ambient temperature for about 12-24 h. The appropriate thiohydantoin VII is then added and the reaction heated under inert atmosphere, preferably in a sealed tube at about 130-140xc2x0 C. for about 1-4 days to provide IX after concentration and purification by silica gel chromatography. An acid, such as trifluoroacetic acid, is added to a solution of IX in a solvent such as dichloroethane and heated under inert atmosphere at about 50-100xc2x0 C. for about 12-24 h to provide I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90CH) after standard workup and purification.
Analogs of I (A1xe2x95x90N, A2xe2x95x90CH) where D is a carbon substituted with various groups, such as halogen, CHO, an alkyl group, an aryl or aryl sulfide, sulfoxide or sulfone, may be prepared as described below and outlined in Scheme III. 
In Scheme III, M is a metal atom such as Li or Mg, Hal is Cl, Br or I and E is a functional group transferable by an electrophilic reagent and can be, but is not restricted to, Cl, Br, I, CN, alkyl, CHO, SO2M, SO2R or CO2R, where R is alkyl or aryl.
The desired N-halosuccinimide (about 1 mole equivalent) is added in portions to a solution of I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90CH), in a suitable solvent such as methylene chloride at about xe2x88x9210xc2x0 C. to ambient temperature, preferably at about 0xc2x0 C., and stirred for about 2 to 15 h. Following workup and purification, I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94Cl, Cxe2x80x94Br, Cxe2x80x94I) is obtained.
The halogen substituted compound I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94Cl, Cxe2x80x94Br, Cxe2x80x94I) may be transformed to an organometallic intermediate I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94M, where M is a metal atom, such as Li or Mg) by treatment with an organometallic reagent, such as an alkyl or aryl lithium or a Grignard reagent. This organometallic intermediate may be reacted with an electrophile, such as an N-chloro, bromo- or iodo-succinimide, tosyl cyanide, an alkyl or aryl sulfonyl chloride, an alkyl or aryl disulfide, an alkyl- or arylthiosulfonate, an alkyl or aryl chloroformate, an alkyl halide, N,N-dimethylformamide or sulfur dioxide, to produce the anolog of I (A1xe2x95x90N, A2xe2x95x90CH) where D is a carbon substituted with various groups, such as Cl, Br, I, CN, an alkyl group, an alkyl or aryl sulfone, an alkyl or aryl sulfide, CHO, or a sulfinate salt. The sulfides may be further oxidized with a reagent, such as potassium peroxymonosulfate, or m-chlorobenzoic acid, to provide sulfoxides or sulfones. The sulfinate salts may be further transformed to produce sulfones and sulfonamides as described below.
More specifically, compounds I (A1xe2x95x90N, A2xe2x95x90CH) with Dxe2x95x90CN may be obtained by treating a solution of the corresponding halide, preferably iodide I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94I), in a solvent such as THF with an alkyl magnesium reagent, such as cyclopentyl magnesium bromide, at about xe2x88x9278 to 0xc2x0 C., preferably about xe2x88x9230 to xe2x88x9240xc2x0 C., under an inert atmosphere, for about 1 to 5 h to generate an organomagnesium species I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94Mg). Tosyl cyanide is then added and the reaction allowed to gradually warm to ambient temperature and to proceed for about 1 to 24 h. Following workup and purification, I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94CN) is obtained.
Compounds I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94SO2R where R=alkyl or aryl) may be obtained by treating the organomagnesium species I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94Mg) as generated above with an alkyl or aryl sulfonyl chloride. Alternatively, one may add an alkyl- or aryldisulfide, or an alkyl- or arylthiosulfonate (prepared by oxidizing the corresponding alkyl or aryl disulfide, for example with m-chloroperoxybenzoic acid in a suitable solvent such as methylene chloride) and then heating the reaction at about the reflux temperature of the solvent for about 1 to 3 h to obtain I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94SR, where R=alkyl or aryl) after workup and purification. The resulting product may be oxidized to the corresponding sulfoxide or sulfone with a suitable oxidizing agent such as potassium peroxymonosulfate or m-chloroperoxybenzoic acid.
Compounds I (A1xe2x95x90N, A2xe2x95x90CH) with Dxe2x95x90Cxe2x80x94CO2R, where R is an alkyl or an aryl group, may be obtained by treating the organomagnesium species as generated above with an appropriate alkyl or aryl chloroformate, in a solvent such as THF, at about xe2x88x9220 to xe2x88x9278xc2x0 C., preferably about xe2x88x9240xc2x0 C., under an inert atmosphere for about 15 min to 1 h before allowing the reaction to warm to room temperature over about 30 min to 1 h. Following quenching, for example with aqueous sodium bicarbonate, workup and purification, I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94CO2R) is obtained.
Compounds I (A1xe2x95x90N, A2xe2x95x90CH) with Dxe2x95x90Cxe2x80x94CHO may be obtained by treating a solution of the corresponding halide, preferably iodide (I: A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94I), in a solvent such as THF with an alkyl lithium, such as n-BuLi at about xe2x88x9250 to xe2x88x92120xc2x0 C., preferably about xe2x88x92100xc2x0 C., under an inert atmosphere for about 15 min to 1 h. N,N-Dimethylformamide is added and the reaction gradually allowed to warm to about 0xc2x0 C. and stirred for about 1 h. Following quenching, for example with aqueous ammonium chloride, workup and purification, I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94CHO) is obtained.
One may also synthesize certain compounds of the invention by treating the organomagnesium intermediate as generated above with sulfur dioxide to generate an intermediate magnesium sulfinate salt. This intermediate may be treated with alkylating reagents, such as alkyl halides to produce additional compounds of the formula I (A1xe2x95x90N, A2xe2x95x90CH ) with Dxe2x95x90Cxe2x80x94SO2R (Rxe2x95x90alkyl). The intermediate magnesium sulfinate salt may also be treated with N-chlorosuccinimide to generate the sulfonyl chloride I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94SO2Cl). The sulfonyl chloride can in turn be treated with amines to produce desired sulfonamides I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90Cxe2x80x94SO2NRRxe2x80x2 where R and Rxe2x80x2=a hydrogen atom, an alkyl or aryl group, or together comprise part of a heterocyclic ring).
Analogs of I (A1xe2x95x90N, A2xe2x95x90CH) with Dxe2x95x90Cxe2x80x94SO2NRRxe2x80x2 where R and Rxe2x80x2 together comprise part of a heterocyclic ring and where R and/or Rxe2x80x2 contains a second nitrogen, for example piperazine, can be further substituted on the second nitrogen, for example with acyl, alkyl, aryl, carbamyl or sulfonyl as described below and outlined in Scheme IV. 
In Scheme IV, Rxe2x80x3 is a functional group transferable by an electrophilic reagent and can be, but is not restricted to, an alkyl group, COR, CONRRxe2x80x2, CO2R, or SO2R, where R or Rxe2x80x2 is alkyl or aryl.
The compound bearing the heteroatom can be treated with reagents such as an alkanoyl or aroyl chloride, alkanoyl or aroyl anhydride, alkyl halide, alkyl or aryl sulfonyl chloride or alkyl or aryl isocyanate to produce compounds where I (A1xe2x95x90N, A2xe2x95x90CH) and D is a carbon substituted with a sulfonamide which itself is further substituted with various groups such as alkyl or aryl amides, alkyl amines, alkyl or aryl sulfonamides, and alkyl or aryl ureas.
More specifically, compounds I (A1xe2x95x90N, A2xe2x95x90CH) and where D is a carbon substituted with a piperazinesulfonamide which itself is further N-acylated may be obtained by treating a solution of the corresponding piperazinesulfonamide, in a solvent such as N,N-dimethylformamide with an appropriate carboxylic acid, in the presence of a coupling agent, such as polystyrene resin-bound carbodiimide, at about 20xc2x0 C. for about 2 to 24 h. Following workup and purification, compounds I (A1xe2x95x90N, A2xe2x95x90CH) and where Dxe2x95x90 is a carbon substituted with an acylated piperazinesulfonamide are obtained.
Alternatively, these compounds may be obtained by treating a solution of the corresponding piperazinesulfonamide, in a solvent such as dichloromethane with an appropriate alkanoyl or aroyl chloride, in the presence of a base, such as triethylamine, at about xe2x88x9220 to 20xc2x0 C., preferably about 0xc2x0 C. for about 15 min to 2 h. Following quenching, for example with aqueous sodium bicarbonate, workup and purification, the desired acylated piperazinesulfonamides are obtained.
Compounds I (A1xe2x95x90N, A2xe2x95x90CH) and where D is a carbon substituted with a piperazinesulfonamide which itself participates additionally in an urea linkage may be obtained by treating a solution of the corresponding piperazinesulfonamide in a solvent such as dichloromethane with an appropriate isocyanate, at about 0 to 40xc2x0 C., preferably about 20xc2x0 C. for about 2 to 24 h. Following workup and purification, compounds I (A1xe2x95x90N, A2xe2x95x90CH) and where Dxe2x95x90 is a carbon substituted with an urea functionalized piperazinesulfonamide are obtained.
Alternatively, compounds I (A1xe2x95x90N, A2xe2x95x90CH) and where D is a carbon substituted with a piperazinesulfonamide which itself is further N-sulfonylated may be obtained by treating a solution of the corresponding piperazinesulfonamide, in a solvent such as dichloromethane with an appropriate sulfonyl chloride, in the presence of a base, such as triethylamine, at about xe2x88x9220 to 20xc2x0 C., preferably about 0xc2x0 C. for about 15 min to 2 h. Following quenching, for example with aqueous sodium bicarbonate, workup and purification, compounds I (A1xe2x95x90N, A2xe2x95x90CH) and where Dxe2x95x90 is a carbon substituted with a sulfonylated piperazinesulfonamide are obtained.
Functional group transformations well known in the art may be employed to modify the substituents on D illustrated above to obtain additional compounds of the invention.
Analogs of I (A1N, Dxe2x95x90CH) where A2 is a carbon substituted with various groups, such as halogen, CN, CHO, an alkyl group, an alkyl or aryl sulfide, sulfoxide or sulfone, may be prepared as described below and outlined in Scheme V. In Scheme V, M is a metal atom, such as Li or Mg, Hal is Cl, Br or I, and E is an functional group transferable by an electrophilic reagent and can be, but is not restricted to, Cl, Br, I, CN, alkyl, CHO, SO2M, SO2R or CO2R, where R is alkyl or aryl. 
The desired N-halosuccinimide (about 2 mole equivalent relative to I) is added in portions to a solution of I (A1xe2x95x90N, A2xe2x95x90CH, Dxe2x95x90CH), in a suitable solvent such as methylene chloride at about xe2x88x9210xc2x0 C. to ambient temperature, preferably at about 0xc2x0 C., and stirred for about 2 to 15 h. Following workup and purification, I (A1xe2x95x90N, A2xe2x95x90Dxe2x95x90Cxe2x80x94Cl, Cxe2x80x94Br or Cxe2x80x94I) is obtained.
The compound I (A1xe2x95x90N, A2xe2x95x90Dxe2x95x90Cxe2x80x94Cl, Cxe2x80x94Br or Cxe2x80x94I) may be treated in a solvent such as THF with an alkyl magnesium bromide, such as cyclopentyl magnesium bromide, at about xe2x88x9278 to 0xc2x0 C., preferably about xe2x88x9230 to xe2x88x9240xc2x0 C., under an inert atmosphere, for about 1 to 5 h. An aqueous acid, such as 1N hydrogen chloride or saturated NH4Cl solution, is then added. Following workup and purification, I (A1xe2x95x90N, A2xe2x95x90Cxe2x80x94Cl, Cxe2x80x94Br or Cxe2x80x94I, and Dxe2x95x90CH) is obtained.
The halogen substituted compound I (A1xe2x95x90N, A2xe2x95x90Cxe2x80x94Cl, Cxe2x80x94Br or Cxe2x80x94I, and Dxe2x95x90CH) may be transformed to an organometallic intermediate I (A1xe2x95x90N, A2xe2x95x90Cxe2x80x94M, Dxe2x95x90CH, where M is an metal atom, such as Li or Mg) by treatment with an organometallic reagent, such as an alkyl or aryl lithium or magnesium reagent. This organometallic intermediate may be reacted with an electrophile, such as an N-chloro-, bromo- or iodo-succinimide, tosyl cyanide, an alkyl halide, an alkyl or aryl sulfonyl chloride, an alkyl or aryl disulfide, an alkyl- or arylthiosulfonate, an alkyl or aryl chloroformate, N,N-dimethylformamide or sulfur dioxide, to produce the analog of I (A1xe2x95x90N, Dxe2x95x90CH) where A2 is a carbon substituted with various groups, such as Cl, Br, I, CN, an alkyl group, an alkyl or aryl sulfone, an alkyl or aryl sulfide, CHO, or a sulfinate salt. The sulfides may be further oxidized with a reagent, such as potassium peroxymonosulfate, or m-chlorobenzoic acid, to sulfoxides or sulfones. The sulfinate salts may also be reacted with an alkylating reagent, such as an alkyl bromide or iodide to produce sulfones. Alternatively, the sulfinate salts may be transformed into the sulfonyl chlorides with a chlorinating reagent, such as NCS. The sulfonyl chlorides may be reacted with an amine to produce sulfonamides I (A1xe2x95x90N, A2xe2x95x90Cxe2x80x94SO2NR1R2, Dxe2x95x90CH).
More specifically, compounds I (A1xe2x95x90N, Dxe2x95x90CH) with A2xe2x95x90Cxe2x80x94CN, Cxe2x80x94SO2R or CO2R, where R is alkyl or aryl, Cxe2x80x94CHO, Cxe2x80x94SO2Cl and Cxe2x80x94SO2NRRxe2x80x2 may be prepared from the corresponding halide or organomagnesium species as described above (Scheme III) for D.
Functional group transformations well known in the art may be employed to modify the substituents on A2 illustrated above to obtain additional compounds of the invention.
Functional group transformations also allow the derivatization of R4. In particular, when R4 is a brominated or iodonated benzyl group, these halogens can often be replaced with aryl groups by techniques known in the art, for example by treating a solution of the halogenated benzyl group, with an organometallic reagent such as an aryl boronate, boronic acid or stannane, in a solvent such as a mixture of toluene and ethanol, in the presence of a base, such as aqueous sodium carbonate, with a metal catalyst, such as Pd(PPh3)4, at about 75 to 110xc2x0 C., preferably about 85xc2x0 C. for about 2 to 24 h. Following workup and purification, I (R4xe2x95x90CH2C4H6Ar) is obtained, where Ar can be, but is not limited to, furyl, phenyl, pyridyl, pyrimidyl and thiophenyl.
Compounds of formula I with A1xe2x95x90A2xe2x95x90Dxe2x95x90N may be prepared as illustrated in Scheme VI and described below. 
Intermediate VII is treated with an alkylating agent such as diethyl sulfate, in a suitable solvent such as aqueous base and THF. After workup and purification, the intermediate is treated with a suitable oxidizing agent such as potassium peroxymonosulfate to give sulfoxide X. A solution of X is then treated with NaN3 at ambient temperature for about 12-24 h. Upon workup and purification, carboxylic acid XI is obtained. Intermediate XI is then reacted under standard peptide coupling conditions, for example treatment with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBT) and a base, such as diisopropylethylamine, in a suitable solvent such as DMF for about 5 to 24 h at ambient temperature. Following workup and purification, I (A1xe2x95x90A2xe2x95x90Dxe2x95x90N ) is obtained.
Compounds of formula I where A1xe2x95x90N, A2xe2x95x90N, and Dxe2x95x90CH may be prepared as illustrated in Scheme VII and described below. 
Intermediate X (Scheme VI) is treated with formic hydrazide in a suitable solvent such as DMSO, under an inert atmosphere at about 50 to 100xc2x0 C. for about 5 to 24 h to provide XII after workup and purification. Intermediate XII is treated with a catalytic amount of an acid, such as p-toluenesulfonic acid in a suitable solvent, such as toluene. Molecular sieves or a trap to collect water formed in the reaction may be employed. The reaction is heated at reflux temperature for about 3 to 12 h. The desired compound of formula I (A1N, A2xe2x95x90N, and Dxe2x95x90CH) is obtained following purification.
Analogs of I (A1xe2x95x90N, A2xe2x95x90N) where Dxe2x95x90C substituted with various groups may be prepared as described above for analogs of I (A1xe2x95x90N, A2xe2x95x90CH).
The invention is further described by the following synthetic examples.